Recent studies have identified small molecule inhibitors of the paracaspase activity of MALT1, a protease and scaffolding protein involved in the B-cell receptor (BCR) signaling pathway, that are effective killing lymphomas in vitro and in vivo in xenograft models of Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL). DLBCL is the most common lymphoma and ABC-DLBCL its most chemoresistant subtype. Moreover, the BCR pathway is involved in cell proliferation and survival of several lymphoma subtypes, including follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia/lymphoma. However, not all ABC-DLBCL cell lines and primary patient samples were equally sensitive to MALT1 inhibitors in vitro. Thus, we hypothesize that response to MALT1 inhibitors will be dependent on the genetic background of ABC-DLBCLs, being those holding mutations downstream of MALT1 more likely to be resistant. Likewise, as already reported for other targeted therapies, acquired resistance mechanisms could arise that prevent response to MALT1 inhibitors by either mutation in MALT1 or its downstream targets or by activation of alternative survival pathways. Moreover, lymphoma therapy with drug combinations is the gold standard for the disease and has been proven most effective, thus we hypothesize that MALT1 inhibition will be most valuable in combination with other chemotherapeutic or targeted therapy agents. Consequently, in order to effectively translate MALT1 inhibitors to the clinical practice, our specific aims are: 1) To determine the genetic background of responders to MALT1 inhibition; 2) To define possible resistance mechanisms that tumors will deploy to escape therapy and 3) To design and test combination therapies using a holistic approach (rational combination based on actual knowledge of the disease, resistance mechanisms found in Aims 1 and 2 and, unbiased high throughput screening).